The Gladstone Institute of Neurological Disease (GIND) at the University of California, San Francisco (UCSF) uses an interdisciplinary teann approach to the investigation of neurodegenerative disorders. Alzheimer's disease (AD) is the main cause of aging-related dementia. Because of the increasing longevity of populations around the world, AD is a medical problem of mounting social and economic impact. Indeed, the predicted increase in AD cases could make our health care system collapse in the not-too-distant future. Unfortunately, available treatments provide only partial and temporary symptomatic relief, and no strategy Is available to prevent or reverse AD. To counteract the rapidly rising prevalence of AD in the US, we propose to recruit an investigator who can advance our ability to develop novel approaches to the treatment and prevention of AD. The new investigator will help us expand our efforts to discover and validate novel drug targets for AD; to screen, develop, and evaluate drugs aimed at such targets; and to develop and explore novel bench-to-bedside models. The successful candidate will have a full faculty position as assistant investigator at Gladstone and a joint appointment as assistant professor in UCSF's Department of Neurology with membership in the University's academic senate. S/he will also have appointments in the Neuroscience Graduate Training Program (a branch Of the Program in Biological Sciences (PIBS) Graduate Training Program), the Biomedical Sciences Graduate Training Program, and the Medical Scientist (MD/PhD) Graduate Training Program at UCSF. These appointments provide ready access to talented graduate students. Although faculty with primary appointments at Gladstone are welcome to teach at UCSF, they do not have specific teaching requirements, which maximizes the amount of time they can devote to research. This arrangement will guarantee that the new investigator can devote at least 75% of time to research. As director of the GIND since its inauguration in 1998 and PI of a recently renewed program project grant focusing on proteinopathies of the aging central nervous system, the PI of this proposal has extensive experience in nurturing the careers of junior faculty and in integrating them into interdisciplinary teams tackling major unresolved biomedical problems. The above constellation makes our application fully responsive to this P30 mechanism and should ensure that we will achieve our goals within the proposed timeframe.